The present invention relates to novel heterocyclic aromatic compounds which stimulate endogenous production and/or release of growth hormone, and to methods for treating obesity, improving bone density (to treat osteoporosis) and stimulating increase in muscle mass and muscle strength employing such compounds.
The pituitary gland secretes growth hormone which stimulates growth in body tissue capable of growing and affects metabolic processes by increasing rate of protein synthesis and decreasing rate of carbohydrate synthesis in cells. Growth hormone also increases mobilization of free fatty acids and use of free fatty acids for energy.
The prior art is replete with patents/applications which disclose compounds which are useful as growth hormone secretagogues.
The following patents/applications, disclose benzofused lactams which are disclosed as being useful in promoting release of growth hormone:
U.S. Pat. Nos. 5,206,235; 5,283,741; 5,284,841; 5,310,737; 5,317,017; 5,374,721; 5,430,144; 5,434,261; 5,438,136; 5,545,735; 5,583,130; 5,606,054; 5,672,596 and 5,726,307; WO 96-05195 and WO 95-16675.
The following patents/applications, disclose diverse chemotypes as being useful in promoting release of growth hormone:
U.S. Pat. Nos. 5,536,716; 5,578,593; 5,622,973; 5,652,235; 5,663,171; WO 94-19367; WO 96-22997; WO 97-24369 and WO 98-58948.
In accordance with the present invention, novel heterocyclic aromatic compounds are provided which are growth hormone secretagogues and have the structure 
including pharmaceutically acceptable salts thereof, prodrug esters thereof, and all stereoisomers thereof,
wherein R1 is alkyl, aryl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyloxyalkyl, aryloxyalkyl, heteroaryl, cycloalkylalkoxyalkyl, heteroarylalkyl, cycloheteroalkyl or cycloheteroalkylalkyl (where the above groups are defined below) and these groups may be optionally substituted by 1,2 or 3-substituents selected from halogen, xe2x80x94OR8, xe2x80x94OC(O)R8, alkyl, phenyl, phenoxy, halophenyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94N(R8a)C(O)(R8), or xe2x80x94N(R8)(R8a);
R1a is H, alkyl, or cycloalkyl;
Xa is heteroaryl, which preferably include 
A is oxygen, sulfur, xe2x80x94NHxe2x80x94, xe2x80x94Nxe2x80x94R5, or xe2x80x94NC(O)xe2x80x94R2;
B is xe2x80x94CR5b or xe2x80x94Nxe2x80x94;
Z is a bond or xe2x80x94Sxe2x80x94;
G is oxygen or sulfur;
U is oxygen, sulfur, xe2x80x94NHxe2x80x94, or xe2x80x94NR5b;
R2 is alkyl, aryl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryl, or heteroarylalkyl (where the above groups are defined below) and these groups may optionally be substituted by 1,2 or 3-substituents selected from halogen, xe2x80x94OR8b, xe2x80x94OC(O)R8b, alkyl, phenyl, phenoxy, halophenyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94N(R8c)C(O)(R8b), or xe2x80x94N(R8c)(R8b);
R3 is H, halogen, alkyl, aryl, alkenyl, alkynyl, alkaryl, alkoxy, aryloxy or J1, and where alkyl, aryl, alkenyl, alkynyl, arylalkyl, alkoxy, or aryloxy may be optionally substituted with 1 to 3 J1;
R4 and R4a are the same or different and are independently H, halogen, xe2x80x94CF3, alkyl, or aryl;
R5 is H, alkyl, aryl, alkenyl, arylalkenyl, alkynyl, arylalkyl, arylalkynyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroaryl, cycloalkylalkoxyalkyl, xe2x80x94SO2T1, xe2x80x94SO2N(T1a)T1, or heteroarylalkyl, and where alkyl, aryl, alkenyl, arylalkenyl, alkynyl, arylalkyl, arylalkynyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, cycloalkylalkoxyalkyl, or heteroarylalkyl may be independently optionally substituted with 1 to 3 J1;
R5a and R5b are the same or different and are independently H, alkyl, aryl, alkenyl, arylalkenyl, alkynyl, arylalkyl, arylalkynyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroaryl, cycloalkylalkoxyalkyl, heteroarylalkyl, or J1, and where alkyl, aryl, alkenyl, arylalkenyl, alkynyl, arylalkyl, arylalkynyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, cycloalkylalkoxyalkyl, or heteroarylalkyl may be independently optionally substituted with 1 to 3 J1;
Y is 
xe2x80x83where x and y are independently 0 to 3 and z is 1 to 3;
Xc is a bond, xe2x80x94Nxe2x80x94R6a or xe2x80x94Oxe2x80x94;
R7 and R7a are the same or different and are independently H, alkyl, xe2x80x94CF3, phenyl, aryl, arylalkyl, and cycloalkyl; or one or both of R7 and R7a can be independently joined to one or both of R9 and R10 groups (of Xb) to form an alkylene bridge of 1 to 5 carbon atoms; or R7 and R7a are joined together to form a ring of from 3-7 carbon atoms;
R6, R6a, R6b, R6c, R8, R8a, R8b, R8c, R8d, R8e, R8f, R8g, R8h, R8i, R8k, R8l, and R8m are the same or different and are independently H, alkyl, cycloalkyl, alkenyl or aryl;
R8j is H, alkyl, aryl, hydroxy or xe2x80x94OC(O)R8k;
Xb is 
R9 and R10 are the same or different and are independently selected from H, alkyl, and substituted alkyl where the substituents may be 1 to 3 hydroxys, 1 to 3 C1-C10-alkanoyloxy; 1 to 3 C1-6 alkoxy, phenyl, phenoxy, C1-C6-alkoxycarbonyl; or R9 and R10 can together form xe2x80x94(CH2)tXd(CH2)uxe2x80x94 where Xd is C(R8h)(R8j), xe2x80x94Oxe2x80x94 or xe2x80x94N(R6b), t and u are independently 1-3;
R11 is H, C1-C6alkyl, xe2x80x94CF3, arylalkyl, or aryl, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxy, 1 to 3 C1-10alkanoyloxy, 1 to 3 C1-6 alkoxy, phenyl, phenoxy or C1-6alkoxycarbonyl;
R12 and R13 are independently H, C1-C6alkyl, xe2x80x94CF3, aryl, or halogen, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxy, 1 to 3 C1-C10-alkanoyloxy, 1 to 3 C1-6 alkoxy, or C1-C6 alkoxycarbonyl;
J1 is nitro, xe2x80x94(CH2)vN(T1a)C(O)T1, xe2x80x94(CH2)vCN, xe2x80x94(CH2)vN(T1a)C(O)OT1, xe2x80x94(CH2)vN(T1a)C(O)N(T1b)T1, xe2x80x94(CH2)vN(T1a)SO2T1, xe2x80x94(CH2)vC(O)N(T1a)T1, xe2x80x94(CH2)vC(O)OT1, xe2x80x94(CH2)vOC(O)OT1, xe2x80x94(CH2)vOC(O)T1, xe2x80x94(CH2)vOC(O)N(T1a)T1, xe2x80x94(CH2)vN(T1a)SO2N(T1b)T1, xe2x80x94(CH2)vOT1, xe2x80x94(CH2)vSO2T1, xe2x80x94(CH2)vSO2N(T1a)T1, xe2x80x94(CH2)vC(O)T1, xe2x80x94(CH2)vCH(OH)T1, cycloheteroalkyl, or heteroaryl as defined below, with v being 0-5;
T1, T1a and T1b are the same or different and are independently H, alkyl, alkenyl, alkynyl, lower alkythioalkyl, alkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, or cycloalkyl, each of which may be optionally substituted with 1, 2 or 3 of the following groups, halogen, hydroxyl, xe2x80x94NR8fC(O)NR8gR8i, xe2x80x94C(O)NR8fR8g, xe2x80x94NR8fC(O)R8g, xe2x80x94CN, xe2x80x94N(R8f)SO2R14, xe2x80x94OC(O)R8f, xe2x80x94SO2NR8fR8g, xe2x80x94SOR14, xe2x80x94SO2R14, alkoxy, xe2x80x94COOH, cycloheteroalkyl, or xe2x80x94C(O)OR14; or T1 and T1a or T1 and T1b can together form xe2x80x94(CH2)wXe(CH2)zxe2x80x94 where Xe is xe2x80x94C(R8m)(R8l), xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NC(O)OR14a, xe2x80x94NC(O)NR14aR4b, xe2x80x94NC(O)R14a or xe2x80x94N(R6c) where w and z are each independently 1-3; with the proviso that T1 can not be hydrogen when it is connected to carbonyl or sulfur, as in xe2x80x94C(O)T1 or xe2x80x94SO2T1;
R14, R14a, and R14b are independently C1-C6alkyl, heteroaryl, or aryl, each optionally substituted with xe2x80x94(CH2)sOH, with s being 0-5;
with the proviso that where Xa is 
(1) where one or both of R7 and R7a, and one or both of R9 and R10 form an alkylene bridge, then where R5 is xe2x80x94(CH2)C(O)N(T1a)T1, then at least one of T1a and T xe2x89xa0H; or
(2) where R1 is arylalkyl and R1a is H and R5 is xe2x80x94(CH2)C(O)N(T1a)T1, then T1a or T1 is other than 
(3) where R1 and R7 are each 2-naphthyl-CH2xe2x80x94, then R5 xe2x89xa0 phenethyl.
The compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in structural formula I. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention. In the case of the asymmetric center represented by the asterisk in formula I, the more active and thus more preferred configuration is R as determined by the R/S rules when R1a is H. Isomers may be separated by conventional methods, for example, chromatographic or fractional crystallization.
The pharmaceutically acceptable salts of the compounds of formulae I of the invention include alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium, as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, ethylenediamine, t-butylamine, t-octylamine, dehydroabietylamine, as well as pharmaceutically acceptable anions such as phosphate, mandelate, chloride, bromide, iodide, tartrate, acetate, methanesulfonate, maleate, succinate, glutarate, and salts of naturally occurring amino acids such as arginine, lysine, alanine and the like, and prodrug esters thereof.
In addition, in accordance with the present invention, a method for increasing levels of endogenous growth hormone or increasing the endogenous production or release of growth hormone is provided wherein a compound of formula I as defined hereinbefore is administered in a therapeutically effective amount.
Furthermore, in accordance with the present invention, a method is provided for preventing or treating osteoporosis (improving bone density and/or strength), or treating obesity, or increasing muscle mass and/or muscle strength, or maintenance of muscle strength and function in elderly humans, or reversal or prevention of fraility in elderly humans, wherein a compound of formula I as defined hereinbefore is administered in a therapeutically effective amount.
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
Unless otherwise indicated, the term xe2x80x9clower alkylxe2x80x9d, xe2x80x9calkylxe2x80x9d or xe2x80x9calkxe2x80x9d as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons, more preferably 1 to 6 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 3 substituents including alkyl, aryl, alkenyl, alkynyl, hydroxy, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, arylalkyloxy, alkanoyl, amino, haloaryl, CF3, OCF3, aryloxy, heteroaryl, cycloalkylalkoxyalkyl, or cycloheteroalkyl.
Unless otherwise indicated, the term xe2x80x9ccycloalkyllxe2x80x9d as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 4 to 7 carbons, forming the ring and which may be fused to 1 aromatic ring as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl, 
any of which groups may be optionally substituted with 1 to 3 substituents as defined above for alkyl.
The term xe2x80x9carylxe2x80x9d, as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl) and may optionally include one to three additional rings fused to xe2x80x9carylxe2x80x9d (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) and may be optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, fluorenyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, oxo, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl, or preferably any of the aryl substituents as set out above.
Preferred aryl groups include phenyl, biphenyl or naphthyl.
The term xe2x80x9caralkylxe2x80x9d, xe2x80x9caryl-alkylxe2x80x9d, or xe2x80x9caryllower alkylxe2x80x9d as used herein alone or as part of another group refers to alkyl groups as discussed above having an aryl substituent, such as benzyl or phenethyl, or naphthylpropyl, or an aryl as defined above.
The term xe2x80x9clower alkoxylxe2x80x9d, xe2x80x9calkoxylxe2x80x9d, xe2x80x9caryloxylxe2x80x9d or xe2x80x9caralkoxyxe2x80x9d l as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.
The term xe2x80x9caminoxe2x80x9d as employed herein alone or as part of another group may optionally be substituted with one or two substituents such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and/or cycloalkyl.
The term xe2x80x9clower alkylthioxe2x80x9d, alkylthioll, xe2x80x9carylthioxe2x80x9d or xe2x80x9caralkylthioxe2x80x9d as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.
The term xe2x80x9clower alkylaminoxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d, xe2x80x9carylaminoxe2x80x9d, or xe2x80x9carylalkylaminoxe2x80x9d as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
The term xe2x80x9cacylxe2x80x9d as employed herein by itself or part of another group, as defined herein, refers to an organic radical linked to a carbonyl 
group; examples of acyl groups include alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, and the like.
The term xe2x80x9calkanoylxe2x80x9d as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.
Unless otherwise indicated, the term xe2x80x9clower alkenylxe2x80x9d or xe2x80x9calkenylxe2x80x9d as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 3 to 12 carbons, and more preferably 2 to 6 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio or any of the substituents for alkyl as set out herein.
Unless otherwise indicated, the term xe2x80x9clower alkynylxe2x80x9d or xe2x80x9calkynylxe2x80x9d as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, or any of the substituents for alkyl as set out herein.
The term xe2x80x9calkylenexe2x80x9d as employed herein alone or as part of another group refers to alkyl groups as defined above having single bonds for attachment to other groups at two different carbon atoms and may optionally be substituted as defined above for xe2x80x9calkylxe2x80x9d.
The terms xe2x80x9calkenylenexe2x80x9d and xe2x80x9calkynylenexe2x80x9d as employed herein alone or as part of another group refer to alkenyl groups as defined above and alkynyl groups as defined above, respectively, having single bonds for attachment at two different carbon atoms.
Examples of (CH2)x, (CH2)y, (CH2)w, (CH2)v, (CH2)s, (CH2)t, (CH2)u or (CH2)z groups (which may include alkylene, alkenylene or alkynylene groups as defined herein, and may optionally include 1, 2, or 3 substituents which may be any of the alkyl substituents set out herein), are as follows: 
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF3, with chlorine or fluorine being preferred.
The term xe2x80x9cmetal ionxe2x80x9d refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.
The term xe2x80x9cheterocyclicxe2x80x9d, xe2x80x9cheterocyclxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d as employed herein alone or as part of another group refers to xe2x80x9cheteroarylxe2x80x9d groups or xe2x80x9ccycloheteroalkylxe2x80x9d groups.
The term xe2x80x9ccycloheteroalkylxe2x80x9d as used herein alone or as part of another group refers to a 4-, 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)p (which is defined above), such as 
and the like. The above groups may include 1 to 4 substituents such as alkyl, halo, oxo and/or any of of the aryl substituents set out herein. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
The term xe2x80x9cheteroarylxe2x80x9d or xe2x80x9cheterocyclicarylxe2x80x9d as used herein alone or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides, such as 
and the like.
The heteroaryl groups may optionally include 1 to 4 substituents such as any of the aryl substituents set out herein. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
The term xe2x80x9cprodrug estersxe2x80x9d of the formula I compounds includes esters of hydroxyls and phenols, such as acetate, benzoate, pivolate, stearoylate, isobutyrate, and the like as known in the art.
General Synthetic Schemes
The compounds of the present invention may be prepared according to the following general synthetic schemes, as well as relevant published literature procedures that are used by the one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples. Unless otherwise specified, the various substituents of the compounds are defined in the same manner as the formula I compound of the invention.
In the following reactions, amide bond forming (peptide coupling) reactions are conducted under standard peptide coupling procedures know in the art. Optimally, the reaction is conducted in a solvent such as dimethylformamide (DMF) at 0xc2x0 C. to room temperature using 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDAC) or (WSC)), 1-hydroxybenzo-triazole hydrate (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) and a base, for example 4-dimethlaminopyridine (DMAP) or Hunig""s base.
Unnatural protected amino acids can be purchased or prepared by standard methods known in the art. Chiral preparations include Meyers, A. G. et al., J. Am. Chem. Soc., 119, 656-673 (1997). O-Alkylated serine derivatives can be formed from serine by known methods, Maligres, P. E. et al., Tetrahedron, 53, 10983-10992 (1997).
The cyclizations to benzimidazoles or benzoxazoles in Schemes 1, 1a, and 1b can be carried out under standard conditions known in the art. Suitable cyclization procedures are described in Nestor, Jr., J. J., J. Med. Chem., 27, 320-5 (1984) and are optimally heating (60-90xc2x0 C.) in an acidic solvent, such as acetic acid. Benzothiazoles can be prepared as in Spitulnik, M. J., Synthesis, 730 (1976), and by other methods known in the art.
Protection and deprotection in the Schemes below may be carried out by procedures generally known in the art. See, for example, T. W. Greene, Protecting Groups in Organic Synthesis, Second Edition, 1991. PG in the Schemes below denotes a nitrogen protecting group, optimally BOC. The BOC group can be removed under acidic conditions, optimally HCl or trifluoroacetic acid.
Reduction of nitro groups in Schemes 1c and 1d can be carried out by methods know in the art. Optimally the reduction can be carried out with H2 in the presence of a catalyst (palladium or platinum).
The arylation reaction covered in Scheme 2 can be performed under the known Suzuki coupling conditions in the literature, or other conditions using the metals zinc or tin known in the art. If the Rx is a chloro, the coupling can be performed as disclosed in Indolese, A. F., Tet. Lett., 38, 3513-3516 (1997) or Shen, W. Tet. Lett., 38, 5575-5578 (1997) using a nickel catalyst.
The tetrazole forming reaction found in Scheme 3 can be carried out under standard conditions known in the art. Suitable procedures are described in Duncia et al. J. Org. Chem., 56, 2395 (1991).
The triazole forming reaction found in Scheme 4 can be carried out under standard conditions known in the art. Suitable procedures are described in Sung, K et al. Heterocyc. Chem., 29, 1101 (1992), Shukla, J. S. et al. Indian J Chem,, 30B, 332 (1991), and Wilson, M. W. et al. Molecular Diversity, 3, 95 (1998).
Other heterocycles can be prepared by methods known to those skilled in the art and by methods found in A. Katritzky, Comprehensive Heterocyclic Chemistry, Volume 1 and Volume 2, Elseveir. Oxazoles can be formed following methods found in Hamada, Y. et al. Tet. Lett., 23, 235-6 (1982). Oxazoles can also be prepared as in Zhang, X. et al. J. Heterocyclic Chem., 34, 1061-4 (1997), and references cited therein. Thiazoles can be prepared following the procedures in Bredenkamp, M. W. et al., Synth. Commun., 2235-2249 (1990) or Aguilar, E., Tet. Lett., 2473-2476 (1994). Oxadiazoles can be prepared as in Borg, S. et al. J. Org. Chem., 60, 3112-3120 (1995).
The transformation of alcohols 69 to azido 70 and 75 to 76 (Schemes 5 and 5a) can be performed by methods known in the art. A single pot procedure described in Thompson, A. S. et al. J Org Chem., 58, 886 (1993), is the optimal transformation.
The imidazoles prepared as shown in Scheme 5 and 5a can be carried out following the procedures given in Chadwick, D. J. et al. J. Chem. Soc. Perkin Trans. I, 481 (1984) and Iddon, B., Heterocycles, 23, 117 (1985).
The tetrazole forming reaction shown in Scheme 6 can be carried out on solid phase resin.
The solid balls in the schemes and examples below are used to designate a solid phase resin, for example 
The resin may be a Merrifield type resin.
Intermediates 28 and 42 can be further transformed as shown previously in Schemes 3. Alternatively, intermediates 28 and 42 can be treated with an acid linked to a resin, such as Merrifield or Rink, to give resin bound amides, which can be cleaved to give compounds VI and IX. The carbamate resin linker depicted in Scheme 6 is only one possible candidate (Hernandez, A. et al. J. Org. Chem., 62, 3153 (1997)).
Compounds in all Schemes except 1b with a terminal xe2x80x94NHxe2x80x94R9 moiety can be transformed by methods known in the art, such as reductive amination or alkylation, to compounds of the form 
The conditions described here for carrying out each step in the general synthetic schemes are conventional and capable of wide variation. They are presented for illustrative purpose only and are not intended as a restriction on the scope of invention.
Final compounds can be easily purified by recrystallization, silica gel chromatography, or reverse phase prep HPLC. In the cases where reverse phase prep HPLC is used, a mixture of solvent A (10% MeOH/90% H2O/0.2% TFA) and solvent B (90% MeOH/10% H2O/0.22% TFA) are used.
Preferred compounds of formula I of the invention include compounds of the structure wherein Xa is as indicated: 
Preferred are compounds of the present invention of the structure I wherein R1 is arylalkyl,arylalkyloxyalkyl, aryloxyalkyl, cycloheteroalkylalkyl, heteroarylalkyl, for example 
R1a is H or alkyl;
xe2x80x83and
(1) Xa is 
xe2x80x83where R5 is alkyl, alkenyl or heteroaryloxy-alkyl, each substituted with J1, and J1 is xe2x80x94(CH2)vOC(O)N(T1a) (T1), xe2x80x94(CH2)vCN, or heteroaryl; or
(2) Xa is 
xe2x80x83where A is NH, R4 and R4a are H and R3 is J1; or
(3) Xa is 
xe2x80x83where B is xe2x80x94Nxe2x80x94; Z is a bond or xe2x80x94Sxe2x80x94; R5a is H, or alkyl or arylalkyl each substituted with 1 to 3 J1; R5 is alkyl optionally substituted with J1;
R6 is H;
Y is 
xe2x80x83where x and y are 0, Xc is a bond, and R7 and R7a are independently alkyl;
Xb is 
R8j is hydroxy or xe2x80x94OC(O)R8k where R8k is alkyl or aryl;
R9 and R10 are independently H and substituted alkyl where the substituents may be 1 or 2 hydroxyls;
J1 is xe2x80x94(CH2)vCN, xe2x80x94(CH2)vN(T1a)SO2T1, xe2x80x94(CH2)vC(O)N(T1a)T1, xe2x80x94(CH2)vN(T1a)C(O)T1, xe2x80x94(CH2)vOC(O)N(T1a)T1, xe2x80x94(CH2)vN(T1a)C(O)N(T1b)T1, or heteroaryl, with v being 0-4;
T1, T1a and T1b are independently alkyl, lower alkythioalkyl, alkoxyalkyl, aryl, arylalkyl, heteroarylalkyl, cycloheteroalkyl, or cycloalkyl, each of which may be optionally substituted with xe2x80x94OC(O)R8f, xe2x80x94C(O)NR8R8a, xe2x80x94(CH2)sOH, with s being 0-2, xe2x80x94SO2NR8R8a, SO2R14, or alkoxy; or T1 and T1a or T1a and T1b can together form xe2x80x94(CH2)wXe(CH2)zxe2x80x94 where Xe is C(R8m) (R8l);
R14 is C1-C6alkyl optionally substituted with xe2x80x94(CH2)vOH, with v being 0-2;
Preferred compounds of the invention include the following: 
More preferred compounds of the invention include the following: 
The growth hormone releasing compounds of formula I can be administered to animals, including man, to release growth hormone in vivo. For example, the compounds can be administered to commercially important animals such as swine, cattle, sheep and the like to accelerate and increase their rate and extent of growth, and to increase milk production in such animals.
The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of formula I in association with a pharmaceutical carrier or diluent. Optionally, the active ingredient of the pharmaceutical compositions can comprise a growth promoting agent in addition to at least one of the compounds of formula I or another composition which exhibits a different activity, e.g., an antibiotic or other pharmaceutically active material.
Growth promoting agents include, but are not limited to, TRH, diethylstilbesterol, theophylline, enkephalins, E series prostaglandins, compounds disclosed in U.S. Pat. No. 3,239,345, e.g., zeranol, and compounds disclosed in U.S. Pat. No. 4,036,979, e.g., sulbenox or peptides disclosed in U.S. Pat. No. 4,411,890.
A still further use of the disclosed compounds of formula I of the invention is in combination with other growth hormone secretagogues such as GHRP-6, GHRP-1 as described in U.S. Pat. No. 4,411,890; and. publications WO 89/07110 and WO 89/07111 and B-HT920 or growth hormone releasing factor and its analogs or growth hormone and its analogs or so matomedins including IGF-1 and IGF-2. A still further use of the disclosed compounds of formula I of the invention is in combination with parathyroid. hormone or a bisphosphonate, such as MK-217 (alendronate), in the treatment of osteoporosis.
A still further use of the disclosed compounds of formula I is in combination with estrogen, testosterone, a selective estrogen receptor modulator, such as tamoxifen or raloxifene, or a selective androgen receptor modulator, such as disclosed in Edwards, J. P. et al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamann, L. G. et al., J. Med. Chem., 42, 210-212 (1999), for the treatment of aspects of Metabolic Syndrome, maintenance of muscle strength and function in elderly humans, reversal or prevention of fraility in elderly humans, stimulation and increase in muscle mass and muscle strength, attenuation of protein catabolic response after a major operation or trauma; reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; improvement in muscle mobility, and maintenance of skin thickness.
As is well known to those skilled in the art, the known and potential uses of growth hormone are varied and multitudinous. Thus, the administration of the compounds of this invention for purposes of stimulating the release of endogenous growth hormone can have the same effects or uses as growth hormone itself. These varied uses of growth hormone may be summarized as follows: stimulating growth hormone release in elderly humans; maintenance of muscle strength and function in elderly humans, reversal or prevention of fraility in elderly humans, prevention of catabolic side effects of glucocorticoids, treatment of osteoporosis, stimulation and increase in muscle mass and muscle strength, stimulation of the immune system, acceleration of wound healing, acceleration of bone fracture repair, treatment of renal failure or insufficiency resulting in growth retardation, treatment goof physiological short stature, including growth hormone deficient children, treatment of short stature associated with chronic illness, treatment of obesity and growth retardation associated with obesity, treating growth retardation associated with Prader-Willis syndrome and Turner""s syndrome; accelerating the recovery and reducing hospitalization of burn patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushings syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients; treatment of osteochondrodysplasias, Noonans syndrome, schizophrenia, depression, Alzheimer""s disease, delayed wound healing, and psychosocial deprivation; treatment of pulmonary dysfunction and ventilator dependency; attenuation of protein catabolic response after a major operation or trauma; reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; treatment of hyperinsulinemia including nesidioblastosis; adjuvant treatment for ovulation induction; to stimulate thymic development and prevent the age-related decline of thymic function; treatment of immunosuppressed patients; improvement in muscle mobility, maintenance of skin thickness, metabolic homeostasis, renal homeostasis in the frail elderly; stimulation of osteoblasts, bone remodeling, and cartilage growth; stimulation of the immune system in companion animals and treatment of disorders of aging in companion animals; growth promotant in livestock; and stimulation of wool growth in sheep.
In addition, the conditions, diseases, and maladies collectively referenced to as xe2x80x9cSyndrome Xxe2x80x9d or Metabolic Syndrome as detailed in Johannsson J. Clin. Endocrinol. Metab., 82, 727-34 (1997), may be treated employing the compounds of the invention.
The compounds of the present invention are agents that are growth hormone secretagogues and can be administered to various mammalian species, such as monkeys, dogs, cats, rats, humans, etc., in need of treatment. These agents can be administered systemically, such as orally or parenterally.
The compounds of the invention can be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable formulation. The above dosage forms will also include the necessary physiologically acceptable carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol), anti-oxidants (ascorbic acid or sodium bisulfite) or the like. Oral dosage forms are preferred, although parenteral intranasal or aerosol forms are quite satisfactory as well.
The dose administered must be carefully adjusted according to the age, weight, and condition of the patient, as well as the route of administration, dosage form and regimen, and the desired result. In general, the dosage forms described above may be administered in amounts from about 0.0001 to about 100 mg/kg or body weight or in an amount within the range from about 1 to about 1000 mg per day, preferably, from about 5 to about 500 mg per day in single or divided doses of one to four times daily.